This invention relates to compounds having the structure ##STR2## in which R is alkyl, aryl, or aralkyl, A is hydrogen, methyl ethyl or a water-soluble cation such as sodium, ammonium, or quaternary ammonium, or amine, B is hydrogen, fluorine, or azido, the bond is saturated when B is fluorine or azido, and is saturated or unsaturated when B is hydrogen, and D is a purine or pyrimidine base. The compounds thus can be considered to be comprised of a 2',3'-dideoxynucleoside molecule covalently bonded to a molecule of phosphonoformic acid partial ester.
Among the most effective drugs available against human immunodeficiency virus (HIV) are those directed against reverse transcriptase, particularly the 2',3'-dideoxynucleosides such as 3'-azidothymidine (AZT) as described by Mitsuya et al., Proc. Natl. Acad. Sci. USA Vol. 82, 7096-7100 (1985). Other agents effective at relatively high concentrations against HIV are salts of phosphonoformic acid (PFA) such as the sodium salt, as described in Sarin et al., Biochem. Pharmacol. Vol 34, 4075-4079 (1985) and by Sandstrom et al., Lancet, Vol. 1, 1480-1482 (1985).
It has also been proposed to employ mixtures of AZT with a very large molar excess of PFA to inhibit replication of HIV or of cytomegalovirus, as described by Eriksson et al., Antimicrob. Agents Chemother. Vol. 33, 633-669 (1989) and by Koshida et al., Antimicrob. Agents Chemother., Vol. 33, 778-780 (1989). Prodrugs of PFA linked to the 5'-hydroxyl of various deoxynucleosides have also been proposed. See Vaghefi, et al. J. Med. Chem., Vol. 29, 1389-1393 (1986); Griengl et al., J. Med. Chem., Vol. 31, 1831-1839 (1988) and Lambert et al., J. Med. Chem., Vol. 32, 367-374 (1989). However, there has been no indication that these prodrugs might have therapeutic activity in cells infected with retroviruses.
It has now been found that a compound having the structure I set forth above and consisting essentially of a phosphonoformic acid partial ester covalently bonded to a 2',3'-dideoxynucleoside in equimolar proportions is more effective than either component alone as an inhibitor of replication of retroviruses, while at the same time exhibiting low toxicity to the host cells.